# The role of impaired mitophagy and mitochondrial dysfunction in glaucomatous neurodegeneration

> **NIH NIH K99** · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · 2022 · $99,363

## Abstract

PROJECT SUMMARY/ABSTRACT:
Primary open angle glaucoma (POAG), the most common form of glaucoma, is characterized by progressive
loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision loss. Elevated intraocular
pressure (IOP) is the major risk factor for POAG. Unfortunately, the underlying pathological mechanisms
responsible for IOP-induced glaucomatous neurodegeneration still remain unclear. The long-term goal of this
proposal is to delineate the molecular pathways governing IOP-induced glaucomatous neurodegeneration and
to develop an effective glaucoma treatment strategy. To this end, we have developed a novel glucocorticoid
(GC)-induced and myocilin-associated mouse models of POAG, replicating human POAG phenotypes.
Importantly, we have identified impaired mitophagy, accumulation of damaged mitochondria and inflammatory
immune cells in the optic nerve of both human and mouse glaucoma. Based upon our preliminary data, we
propose to: 1) examine the effect of IOP on mitophagy impairment and accumulation of damaged mitochondria
using mouse and human POAG, 2) examine the role of impaired mitophagy on glaucomatous neurodegeneration
and, 3) further identify whether enhancing mitophagy alleviates neurodegeneration and prevent RGC loss in
mouse models of POAG. In the mentored phase, I will establish mouse models to study mitophagy in POAG
including mitophagy reporter transgenic Mt-Keima mice, RGC-specific Parkin and ATG5 conditional knockout
mice under the guidance of Dr. Gulab Zode (an expert in chronic ER stress and autophagy in trabecular
meshwork). In collaboration with Dr. Denise Inman (an expert in the field of mitochondrial metabolism), I will
enhance my understanding of mitochondrial dysfunction in mouse models of POAG. The mentored phase will
also be supplemented by training with Dr. Abbot Clark (well-known leading glaucoma expert), who will provide
assistance with human tissues as well as an additional training for my independent career. Furthermore, regular
meetings with Dr. Paula Gregory who has tremendous experience in assisting young investigators will help me
to develop independent career. During the independent phase, we will examine role of mitophagy on
inflammatory neurodegeneration and determine whether inducing mitophagy (Urolithin A/Actinonin/Metformin/
Parkin overexpression) rescues GC or myocilin-associated POAG. Additionally, during the mentored phase, I
will be having regular meetings with my advisory committee, attend scientific conferences, and continue my
career development. I am in the ideal environment for the proposed research and for my career development as
Dr. Zode has an established state-of-the-art facilities at the North Texas Eye Research Institute, and
collaborations with renowned scientists, Dr. Val Sheffield, Dr. John Hulleman and Dr. Kevin Park. This will help
me to set-up good collaborations, learn new techniques, and build an independent research laboratory at a well-
established...

## Key facts

- **NIH application ID:** 10489339
- **Project number:** 5K99EY032982-02
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
- **Principal Investigator:** Prabhavathi Maddineni
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $99,363
- **Award type:** 5
- **Project period:** 2021-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489339

## Citation

> US National Institutes of Health, RePORTER application 10489339, The role of impaired mitophagy and mitochondrial dysfunction in glaucomatous neurodegeneration (5K99EY032982-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10489339. Licensed CC0.

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